Loss of the candidate tumor suppressor ZEB1 (TCF8, ZFHX1A) in Sézary syndrome. Issue 12 (December 2018)

• Record Type: Journal Article
• Authors: Caprini, Elisabetta; Bresin, Antonella; Cristofoletti, Cristina; Helmer Citterich, Mauro; Tocco, Valeria; Scala, Enrico; Monopoli, Alessandro; Benucci, Roberto; Narducci, Maria; Russo, Giandomenico
• Is Part Of: Cell death and disease. Volume 9:Issue 12(2018)
• Page Start: 1
• Page End: 15
• Publication Date: 2018-12
• Subjects: Cell death -- Periodicals; Apoptosis -- Periodicals; 571.936
• DOI: 10.1038/s41419-018-1212-7
• Languages: English
• ISSNs: 2041-4889

Abstract

Abstract Cutaneous T-cell lymphoma is a group of incurable extranodal non-Hodgkin lymphomas that develop from the skin-homing CD4+ T cell. Mycosis fungoides and Sézary syndrome are the most common histological subtypes. Although next-generation sequencing data provided significant advances in the comprehension of the genetic basis of this lymphoma, there is not uniform consensus on the identity and prevalence of putative driver genes for this heterogeneous group of tumors. Additional studies may increase the knowledge about the complex genetic etiology characterizing this lymphoma. We used SNP6 arrays and GISTIC algorithm to prioritize a list of focal somatic copy-number alterations in a dataset of multiple sequential samples from 21 Sézary syndrome patients. Our results confirmed a prevalence of significant focal deletions over amplifications: single well-known tumor suppressors, such asTP53, PTEN, andRB1, are targeted by these aberrations. In our cohort, ZEB1 (TCF8, ZFHX1A ) spans a deletion having the highest level of significance. In a larger group of 43 patients, we found thatZEB1 is affected by deletions and somatic inactivating mutations in 46.5% of cases; also, we found potentially relevantZEB1 germline variants. The survival analysis shows a worse clinical course for patients withZEB1 biallelic inactivation. Multiple abnormal expression signatures were found associated withZEB1 depletion in Sézary patients we verified thatZEB1 exerts a role in oxidative response of Sézary cells. Our data confirm the importance of deletions in the pathogenesis of cutaneous T-cell lymphoma. The characterization ofZEB1 abnormalities in Sézary syndrome fulfils the criteria of a canonical tumor suppressor gene. Although additional confirmations are needed, our findings suggest, for the first time, thatZEB1 germline variants might contribute to the risk of developing this disease. Also, we provide evidence thatZEB1 activity in Sézary cells, influencing the reactive oxygen species production, affects cell viability and apoptosis.